Cellular and Molecular Bioengineering

, Volume 8, Issue 3, pp 455–470 | Cite as

Micelle Delivery of Parthenolide to Acute Myeloid Leukemia Cells

  • Michael P. Baranello
  • Louisa Bauer
  • Craig T. Jordan
  • Danielle S. W. Benoit
Article
First Online:
Received:
Accepted:

Abstract

Parthenolide (PTL) has shown great promise as a novel anti-leukemia agent as it selectively eliminates acute myeloid leukemia (AML) blast cells and leukemia stem cells (LSCs) while sparing normal hematopoietic cells. This success has not yet translated to the clinical setting because PTL is rapidly cleared from blood due to its hydrophobicity. To increase the aqueous solubility of PTL, we previously developed micelles formed from predominantly hydrophobic amphiphilic diblock copolymers of poly(styrene-alt-maleic anhydride)-b-poly(styrene) (e.g., PSMA100-b-PS258) that exhibit robust PTL loading (75% efficiency, 11% w/w capacity) and release PTL over 24 h. Here, PTL-loaded PSMA-b-PS micelles were thoroughly characterized in vitro for PTL delivery to MV4-11 AML cells. Additionally, the mechanisms governing micelle-mediated cytotoxicity were examined in comparison to free PTL. PSMA-b-PS micelles were taken up by MV4-11 cells as evidenced by transmission electron microscopy and flow cytometry. Specifically, MV4-11 cells relied on clathrin-mediated endocytosis, rather than caveolae-mediated endocytosis and macropinocytosis. In addition, PTL-loaded PSMA-b-PS micelles exhibited a dose-dependent cytotoxicity towards AML cells and were capable of reducing cell viability by 75% at 10 μM PTL, while unloaded micelles were nontoxic. At 10 μM PTL, the cytotoxicity of PTL-loaded micelles increased gradually over 24 h while free PTL achieved maximal cytotoxicity between 2 and 4 h, demonstrating micelle-mediated delivery of PTL to AML cells and stability of the drug-loaded micelle even in the presence of cells. Both free PTL and PTL-loaded micelles induced NF-κB inhibition at 10 μM PTL doses, demonstrating some mechanistic similarities in cytotoxicity. However, free PTL relied more heavily on exofacial free thiol interactions to induce cytotoxicity than PTL-loaded micelles; free PTL cytotoxicity was reduced by over twofold when cell surface free thiols were depleted, where PTL-loaded micelle doses were unaffected by cell surface thiol modulation. The physical properties, stability, and efficacy of PTL-loaded PSMA-b-PS micelles support further development of a leukemia therapeutic with greater bioavailability and the potential to eliminate LSCs.

Keywords

Nanoparticle Drug delivery Endocytosis Leukemia 
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Notes

Acknowledgments

The authors gratefully acknowledge Cheryl Corbett for helpful advice on in vitro assays and Karen Bentley, M.S., of the University of Rochester Medical Center Electron Microscopy Shared Laboratory for sample preparation and EM image acquisition. This work was supported by Alex’s Lemonade Stand Foundation for Childhood Cancer, the I Care I Cure Foundation, and the Leukemia Research Foundation (D.S.W.B.), and the National Science Foundation Graduate Research Fellowship Program (M.P.B.).

Conflict of interest

Michael P. Baranello, Louisa Bauer, Craig T. Jordan, Ph.D., and Danielle S.W. Benoit, Ph.D. each declare no conflicts of interest associated with this work.

Ethical Standards

Neither animal studies nor human studies were carried out by the authors for data reported herein.

Supplementary material

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Supplementary material 1 (TIFF 4824 kb)
12195_2015_391_MOESM2_ESM.tiff (259 kb)
Supplementary material 2 (TIFF 260 kb)
12195_2015_391_MOESM3_ESM.tiff (4.4 mb)
Supplementary material 3 (TIFF 4524 kb)

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Copyright information

© Biomedical Engineering Society 2015

Authors and Affiliations

  • Michael P. Baranello
    • 1
  • Louisa Bauer
    • 2
  • Craig T. Jordan
    • 3
  • Danielle S. W. Benoit
    • 1
    • 2
    • 4
  1. 1.Department of Chemical EngineeringUniversity of RochesterRochesterUSA
  2. 2.Department of Biomedical EngineeringUniversity of RochesterRochesterUSA
  3. 3.Division of HematologyUniversity of Colorado DenverDenverUSA
  4. 4.Center for Musculoskeletal ResearchUniversity of RochesterRochesterUSA

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